4-Heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein

ABSTRACT

Hetero-tetrahydroquinolines can be prepared either by condensing correspondingly substituted hetero-tetrahydroquinoline aldehydes with the desired substituent or by reducing the corresponding keto-substituted hetero-tetrahydroquinolines, followed by introduction of the desired substituent by customary methods. The hetero-tetrahydroquinolines are suitable for use as active compounds in medicaments, in particular in medicaments for treating artheriosclerosis and dyslipidaemias.

This application is a division of U.S. patent application Ser. No.09/999,233, filed Oct. 31, 2001, now U.S. Pat. No. 6,958,346.

The present invention relates to hetero-tetrahydroquinolines, toprocesses for their preparation and to their use in medicaments.

The publication U.S. Pat. No. 5,169,857-A2 discloses 7-(polysubstitutedpyridyl)-6-heptenoates for treating arteriosclerosis, lipoproteinaemiaand hyperproteinaemia. Moreover, the preparation of7-(4-aryl-3-pyridyl)-3,5-dihydroxy-6-heptenoates is described in thepublication EP-325 130-A2. Furthermore, the compound5(6H)-quinolone,3-benzyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl is knownfrom the publication Khim. Geterotsikl. Soedin. (1967), (6), 1118–1120.

The present invention relates to hetero-tetrahydroquinolines of thegeneral formula (I)

in which

-   A represents cycloalkyl having 3 to 8 carbon atoms or represents a    5- to 7-membered saturated, partially unsaturated or unsaturated,    optionally benzo-fused heterocycle having up to 3 heteroatoms from    the group consisting of S, N and O which, in the case of a saturated    heterocycle with a nitrogen function, is optionally also attached    via this function, and where the abovementioned ring systems are    optionally substituted up to 5 times by identical or different    substituents from the group consisting of halogen, nitro, hydroxyl,    trifluoromethyl, trifluoromethoxy and straight-chain or branched    alkyl, acyl, hydroxyalkyl or alkoxy having in each case up to 7    carbon atoms, or by a group of the formula —NR³R⁴,    -   in which    -   R³ and R⁴ are identical or different and represent hydrogen,        phenyl or straight-chain or branched alkyl having up to 6 carbon        atoms,-   or-   A represents a radical of the formula

-   D represents aryl having 6 to 10 carbon atoms which is optionally    substituted by phenyl, nitro, halogen, trifluoromethyl or    trifluoromethoxy, or    -   represents a radical of the formula

-   -   in which    -   R⁵, R⁶ and R⁹ independently of one another represent cycloalkyl        having 3 to 6 carbon atoms, or        -   represent aryl having 6 to 10 carbon atoms or represent a 5-            to 7-membered optionally benzo-fused saturated or            unsaturated mono-, bi- or tricyclic hetreocycle having up to            4 heteroatoms from the group consisting of S, N and O,        -   where the cycles are optionally substituted, in the case of            the nitrogen-containing rings also via the N function, up to            5 times by identical or different substituents from the            group consisting of halogen, trifluoromethyl, nitro,            hydroxyl, cyano, carboxyl, trifluoromethoxy, and            straight-chain or branched acyl, alkyl, alkylthio,            alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up            to 6 carbon atoms, by aryl or trifluoromethyl-substituted            aryl having in each case 6 to 10 carbon atoms or by an            optionally benzo-fused aromatic 5- to 7-membered heterocycle            having up to 3 heteroatoms from the group consisting of S, N            and O,        -   and/or by a group of the formula —OR¹⁰, —SR¹¹, —SO₂R¹² or            —NR¹³R¹⁴,        -   in which        -   R¹⁰, R¹¹ and R¹² independently of one another represent aryl            having 6 to 10 carbon atoms which for its part is            substituted up to 2 times by identical or different            substituents from the group consisting of phenyl, halogen            and straight-chain or branched alkyl having up to 6 carbon            atoms,        -   R¹³ and R¹⁴ are identical or different and have the meaning            of R³ and R⁴ given above,        -   or        -   R⁵ and/or R⁶ represent(s) a radical of the formula

-   -   R⁷ represents hydrogen or halogen,    -   and    -   R⁸ represents hydrogen, halogen, azido, trifluoromethyl,        hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or        alkyl having in each case up to 6 carbon atoms or a radical of        the formula —NR¹⁵R¹⁶,        -   in which        -   R¹⁵ and R¹⁶ are identical or different and have the meaning            of R³ and R⁴ given above,    -   or    -   R⁷ and R⁸ together form a radical of the formula ═O or ═NR¹⁷,        -   in which        -   R¹⁷ represents hydrogen or straight-chain or branched alkyl,            alkoxy or acyl having in each case up to 6 carbon atoms,        -   L represents a straight-chain or branched alkylene or            alkenylene chain having in each case up to 8 carbon atoms            which are optionally substituted up to 2 times by hydroxyl,        -   T and X are identical or different and represent a            straight-chain or branched alkylene chain having up to 8            carbon atoms,        -   or        -   T or X represents a bond,        -   V represents an oxygen or sulphur atom or represents an            —NR¹⁸ group,            -   in which            -   R¹⁸ represents hydrogen or straight-chain or branched                alkyl having up to 6 carbon atoms or phenyl,    -   E represents cycloalkyl having 3 to 8 carbon atoms, or        represents straight-chain or branched alkyl having up to 8        carbon atoms which is optionally substituted by cycloalkyl        having 3 to 8 carbon atoms or hydroxyl, or represents phenyl        which is optionally substituted by halogen or trifluoromethyl,    -   R¹ and R² together form a straight-chain or branched alkylene        chain having up to 7 carbon atoms which has to be substituted by        a carbonyl group and/or by a radical of the formula

-   -   -   in which        -   a and b are identical or different and represent a number 1,            2 or 3,        -   R¹⁹ represents hydrogen, cycloalkyl having 3 to 7 carbon            atoms, straight-chain or branched silylalkyl having up to 8            carbon atoms or straight-chain or branched alkyl having up            to 8 carbon atoms which is optionally substituted by            hydroxyl, straight-chain or branched alkoxy having up to 6            carbon atoms or by phenyl which for its part may be            substituted by halogen, nitro, trifluoromethyl,            trifluoromethoxy or by phenyl or tetrazole-substituted            phenyl,            -   and alkyl is optionally substituted by a group of the                formula —OR²²,            -   in which            -   R²² represents straight-chain or branched acyl having up                to 4 carbon atoms or benzyl.        -   or        -   R¹⁹ represents straight-chain or branched acyl having up to            20 carbon atoms or benzoyl which is optionally substituted            by halogen, trifluoromethyl, nitro or trifluoromethoxy, or            represents straight-chain or branched fluoroacyl having up            to 8 carbon atoms and 9 fluorine atoms,        -   R²⁰ and R²¹ are identical or different, represent hydrogen,            phenyl or straight-chain or branched alkyl having up to 6            carbon atoms,        -   or        -   R²⁰ and R²¹ together form a 3 to 6-membered carbocycle and,            if appropriate also geminally, the carbocycles formed are            optionally substituted up to 6 times by identical or            different substituents from the group consisting of            trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl,            nitro, azido, cyano, cycloalkyl or cycloalkyloxy having in            each case 3 to 7 carbon atoms, straight-chain or branched            alkoxycarbonyl, alkoxy or alkylthio having in each case up            to 6 carbon atoms and straight-chain or branched alkyl            having up to 6 carbon atoms which for its part is            substituted up to 2 times by identical or different            substituents from the group consisting of hydroxyl,            benzyloxy, trifluoromethyl, benzoyl, straight-chain or            branched alkoxy, oxyacyl or carboxyl having in each case up            to 4 carbon atoms and phenyl which for its part may be            substituted by halogen, trifluoromethyl or trifluoromethoxy,            -   and/or the carbocycles formed are optionally                substituted, also geminally, up to 5 times by identical                or different substituents from the group consisting of                phenyl, benzoyl, thiophenyl and sulphonylbenzyl which                for their part are optionally substituted by halogen,                trifluoromethyl, trifluoromethoxy or nitro,            -   and/or are optionally substituted by a radical of the                formula

-   -   -   -   in which            -   c represents a number 1, 2, 3 or 4,            -   d represents a number 0 or 1,            -   R²³ and R²⁴ are identical or different and represent                hydrogen, cycloalkyl having 3 to 6 carbon atoms,                straight-chain or branched alkyl having up to 6 carbon                atoms, benzyl or phenyl which is optionally substituted                up to 2 times by identical or different substituents                from the group consisting of halogen, trifluoromethyl,                cyano, phenyl and nitro,                -   and/or the carbocycles formed are optionally                    substituted by a spiro-linked radical of the formula

-   -   -   -   -   in which                -   W represents either an oxygen or a sulphur atom,                -   Y and Y′ together form a 2- to 6-membered                    straight-chain or branched alkylene chain,                -   e represents a number 1, 2, 3, 4, 5, 6 or 7,                -   f represents a number 1 or 2,                -   R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ are identical                    or different and represent hydrogen,                    trifluoromethyl, phenyl, halogen or straight-chain                    or branched alkyl or alkoxy having in each case up                    to 6 carbon atoms,                -   or                -   R²⁵ and R²⁶ or R²⁷ and R²⁸ in each case together                    form a straight-chain or branched alkyl chain having                    up to 6 carbon atoms,                -   or                -   R²⁵ and R²⁶ or R²⁷ and R²⁸ in each case together                    form a radical of the formula

-   -   -   -   -    in which                -   W is as defined above,                -   g represents a number 1, 2, 3, 4, 5, 6 or 7,                -   R³² and R³³ together form a 3- to 7-membered                    heterocycle which contains an oxygen or sulphur atom                    or a group of the formula SO, SO₂ or —NR³⁴,                -    in which                -    R³⁴ represents hydrogen, phenyl, benzyl or                    straight-chain or branched alkyl having up to 4                    carbon atoms,

    -   and their salts and N-oxides.

The hetero-tetrahydroquinolines according to the invention can also bepresent in the form of their salts. In general, salts with organic orinorganic bases or acids may be mentioned here.

In the context of the present invention, preference is given tophysiologically acceptable salts. Physiologically acceptable salts ofthe compounds according to the invention can be salts of the substancesaccording to the invention with mineral acids, carboxylic acids orsulphonic acids. Particular preference is given, for example, to saltswith hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoricacid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonicacid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts ofthe compounds according to the invention which have a free carboxylgroup. Particular preference is given, for example, to sodium salts,potassium salts, magnesium salts or calcium salts, and also to ammoniumsalts which are derived from ammonia or organic amines, such as, forexample, ethylamine, di- or triethylamine, di- or triethanolamine,dicyclohexylamine, dimethylaminoethanol, arginine, lysine,ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can exist in stereoisomericforms which are either like image and mirror image (enantiomers), orwhich are not like image and mirror image (diastereomers). The inventionrelates both to the enantiomers or diastereomers and to their respectivemixtures. These mixtures of the enantiomers and diastereomers can beseparated into the stereoisomerically uniform components in a knownmanner.

In the context of the invention, a 3- to 8-membered saturatedcarbocyclic ring represents a cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl ring. Preference is given to acyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. Particularpreference is given to cyclobutyl, cyclopentyl or cyclohexyl.

In the context of the invention, heterocycle generally represents asaturated, partially unsaturated or unsaturated, optionally benzo-fused5- to 7-membered, preferably 5- to 6-membered, heterocycle which maycontain up to 3 heteroatoms from the group consisting of S, N and O.Examples which may be mentioned are: indolyl, isoquinolyl, quinolyl,benzo[b]thiophene, benzo[b]furanyl, pyridyl, thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Preference isgiven to quinolyl, furyl, pyridyl and thienyl.

Preference is given to the compounds of the general formula (I)according to the invention,

in which

-   A represents cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl,    cyclooctyl or cyclohexyl, or    -   represents thienyl, imidazolyl, pyrrole, furryl, pyridyl,        morpholine, pyrimidyl or pyridazinyl, which are optionally        substituted up to 2 times by identical or different substituents        from the group consisting of fluorine, chlorine, bromine, amino,        hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain        or branched alkyl, and alkoxy having in each case up to 6 carbon        atoms,-   or-   A represents a radical of the formula

-   D represents phenyl which is optionally substituted by nitro,    fluorine, chlorine, bromine, phenyl, trifluoromethyl or    trifluoromethoxy, or represents a radical of the formula

-   in which-   R⁵, R⁶ and R⁹ independently of one another represent cyclopropyl,    cyclopentyl or cyclohexyl, or    -   represent phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl,        pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl,        benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl        or purin-8-yl,    -   where the cycles are optionally substituted up to 3 times, in        the case of the nitrogen-containing rings also via the N        function, by identical or different substituents from the group        consisting of fluorine, chlorine, bromine, trifluoromethyl,        hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or        branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or        alkoxycarbonyl having in each case up to 4 carbon atoms,        triazolyl, tetrazolyl, benzoxathiazolyl,        trifluoromethyl-substituted phenyl and phenyl,-   or-   R⁷ represents hydrogen, fluorine, chlorine or bromine,-   and-   R⁸ represents hydrogen, fluorine, chlorine, bromine, azido,    trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or    branched alkoxy or alkyl having in each case up to 5 carbon atoms or    a radical of the formula —NR¹⁵R¹⁶,    -   in which    -   R¹⁵ and R¹⁶ are identical or different and represent hydrogen,        phenyl or straight-chain or branched alkyl having up to 4 carbon        atoms,-   or-   R⁷ and R⁸ together form a radical of the formula ═O or ═NR¹⁷,-   in which-   R¹⁷ represents hydrogen or straight-chain or branched alkyl, alkoxy    or acyl having in each case up to 4 carbon atoms,-   L represents a straight-chain or branched alkylene or alkenylene    chain having in each case up to 6 carbon atoms which are optionally    substituted up to 2 times by hydroxyl,-   T and X are identical or different and represent a straight-chain or    branched alkylene chain having up to 6 carbon atoms,-   or-   T or X represents a bond,-   V represents an oxygen or sulphur atom or represents a group of the    formula —NR¹⁸—,    -   in which        -   R¹⁸ represents hydrogen or straight-chain or branched alkyl            having up to 4 carbon atoms or phenyl,-   E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or    -   represents straight-chain or branched alkyl having up to 6        carbon atoms which is optionally substituted by cyclopropyl,        -butyl, -hexyl, -pentyl, -heptyl or by hydroxyl, or represents        phenyl which is optionally substituted by fluorine, chlorine or        trifluoromethyl,-   R¹ and R² together form a straight-chain or branched alkylene chain    having up to 6 carbon atoms which has to be substituted by a    carboxyl group and/or by a radical of the formula

-   -   in which    -   a and b are identical or different and represent a number 1, 2        or 3,    -   R¹⁹ represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl,        straight-chain or branched silylalkyl having up to 7 carbon        atoms or straight-chain or branched alkyl having up to 6 carbon        atoms which is optionally substituted by hydroxyl,        straight-chain or branched alkoxy having up to 4 carbon atoms or        by phenyl which for its part may be substituted by fluorine,        chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or        by phenyl or tetrazole-substituted phenyl,        -   and alkyl is optionally substituted by a group of the            formula —OR²²,        -   in which        -   R²² represents straight-chain or branched acyl having up to            3 carbon atoms or benzyl,    -   or    -   R¹⁹ represents straight-chain or branched acyl having up to 18        carbon atoms or benzoyl which is optionally substituted by        fluorine, chlorine, bromine, trifluoromethyl, nitro or        trifluoromethoxy, or        -   represents straight-chain or branched fluoroacyl having up            to 6 carbon atoms,    -   R²⁰ and R²¹ are identical or different, represent hydrogen,        phenyl or straight-chain or branched alkyl having up to 4 carbon        atoms,    -   or    -   R²⁰ and R²¹ together form a cyclpropyl, cyclobutyl, cyclopentyl,        cyclohexyl or cycloheptyl ring,        -   and the carbocycles formed are optionally substituted, if            appropriate, also geminally, up to 5 times by identical or            different substituents from the group consisting of            trifluoromethyl, hydroxyl, carboxyl, azido, fluorine,            chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl,            cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy,            cyclohexyloxy, straight-chain or branched alkoxycarbonyl,            alkoxy or alkylthio having in each case up to about S carbon            atoms and straight-chain or branched alkyl having up to 5            carbon atoms which for its part is substituted up to 2 times            by identical or different substituents from the group            consisting of hydroxyl, benzyloxy, benzoyl, straight-chain            or branched alkoxy or oxyacyl having in each case up to 3            carbon atoms, trifluoromethyl and phenyl which for its part            may be substituted by fluorine, chlorine, bromine,            trifluoromethyl or trifluoromethoxy,        -   and/or the carbocycles formed are optionally substituted,            also geminally, up to 4 times by identical or different            substituents from the group consisting of phenyl, benzoyl,            thiophenyl and sulphonylbenzyl which for their part are            optionally substituted by fluorine, chlorine, bromine,            trifluoromethyl, trifluoromethoxy or nitro,        -   and/or are optionally substituted by a radical of the            formula

-   -   -   in which        -   c represents a number 1, 2, 3 or 4,        -   d represents a number 0 or 1,        -   R²³ and R²⁴ are identical or different and represent            hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,            straight-chain or branched alkyl having up to 5 carbon            atoms, benzyl or phenyl which is optionally substituted by            fluorine, chlorine, bromine, phenyl or trifluoromethyl,        -   and/or the carbocycles formed are optionally substituted by            a spiro-linked radical of the formula

-   -   -   in which        -   W represents either an oxygen or a sulphur atom,        -   Y and Y′ together form a 2- to 5-membered straight-chain or            branched alkyl chain,        -   e represents a number 1, 2, 3, 4, 5 or 6,        -   f represents a number 1 or 2,        -   R²⁵R²⁶, R²⁷ and R²⁸ are identical or different and represent            hydrogen, trifluoromethyl, phenyl, fluorine, chlorine,            bromine or straight-chain or branched alkyl or alkoxy having            in each case up to 5 carbon atoms,        -   or        -   R²⁵ and R²⁶ or R²⁷ and R²⁸ in each case together form a            straight-chain or branched alkyl chain having up to 5 carbon            atoms or        -   or        -   R²⁵ and R²⁶ or R²⁷ and R²⁸ in each case together form a            radical of the formula

-   -   -   -   in which            -   W is as defined above,            -   g represents a number 1, 2, 3, 4, 5 or 6,

    -   and their salts and N-oxides.

Particular preference is given to compounds of the general formula (I)according to the invention,

in which

-   A represents cyclopropyl, cyclopentyl or cyclohexyl, or    -   represents thienyl or pyridyl which are optionally substituted        up to 2 times by identical or different substituents from the        group consisting of fluorine, chlorine, bromine, hydroxyl,        trifluoromethyl, trifluoromethoxy and straight-chain or branched        alkyl or alkoxy having in each case up to 5 carbon atoms,-   or-   A represents a radical of the formula

-   D represents phenyl which is optionally substituted by nitro,    trifluoromethyl phenyl, fluorine, chlorine or bromine, or    -   represents a radical of the formula

-   -   in which    -   R⁵, R⁶ and R⁹ independently of one another represent        cyclopropyl, cyclopentyl or cyclohexyl, or        -   represent phenyl, naphthyl or pyridyl,        -   where the cycles optionally up to 2 times by identical or            different substituents from the group consisting of            fluorine, chlorine, trifluoromethyl, hydroxyl, cyano,            carboxyl, trifluoromethoxy and straight-chain or branched            alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl            having in each case up to 4 carbon atoms,    -   or    -   R⁷ represents hydrogen or fluorine,    -   and    -   R⁸ represents hydrogen, fluorine, chlorine, bromine, azido,        trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain        or branched alkoxy or alkyl having in each case up to 4 carbon        atoms or a radical of the formula —NR¹⁵R¹⁶,        -   in which        -   R¹⁵ and R¹⁶ are identical or different and represent            hydrogen or straight-chain or branched alkyl having up to 3            carbon atoms,        -   or        -   R⁷ and R⁸ together represent a radical of the formula ═O,        -   L represents a straight-chain or branched alkylene or            alkenylene chain having in each case up to 5 carbon atoms            which are optionally substituted up to 2 times by hydroxyl,        -   T and X are identical or different and represent a            straight-chain or branched alkylene chain having up to 3            carbon atoms,        -   or        -   T or X represents a bond,        -   V represents an oxygen or sulphur atom or a group of the            formula —NR¹⁸,            -   in which        -   R¹⁸ represents hydrogen or straight-chain or branched alkyl            having up to 3 carbon atoms,

-   E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl which    is optionally substituted by fluorine or trifluoromethyl, or    -   represents straight-chain or branched alkyl having up to 4        carbon atoms which is optionally substituted by hydroxyl,

-   R¹ and R² together form a straight-chain or branched alkylene chain    having up to 5 carbon atoms which has to be substituted by a    carbonyl group and/or a radical of the formula —OR¹⁹,    -   in which    -   R¹⁹ represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl,    -   or    -   R¹⁹ represents straight-chain or branched acyl having up to 15        carbon atoms or benzoyl which is optionally substituted by        fluorine, chlorine, bromine, trifluoromethyl, nitro or        trifluoromethoxy, or        -   represents a radical of the formula —Si(CH₃)₂C(CH₃)₃,        -   and the carbocycles formed are optionally substituted, if            appropriate also geminally, up to 4 times by identical or            different substituents from the group consisting of            fluorine, hydroxyl, trifluoromethyl, carboxyl, azido,            chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl,            cyclopentyl, cyclohexyl, cyclopropyloxy, cyclopentyloxy,            cyclohexyloxy, straight-chain or branched alkoxycarbonyl,            alkoxy or alkylthio having in each case up to 4 carbon atoms            and straight-chain or branched alkyl having up to 4 carbon            atoms which for its part is substituted up to 2 times by            identical or different substituents from the group            consisting of hydroxyl, benzyloxy, trifluoromethyl, benzoyl,            methoxy, oxyacetyl and phenyl which for its part may be            substituted by fluorine, chlorine, bromine, trifluoromethyl            or trifluoromethoxy,        -   and/or the carbocycles formed are optionally substituted,            also geminally, up to 4 times by identical or different            substituents from the group consisting of phenyl, benzoyl,            thiophenyl and sulphonylbenzyl which for their part are            optionally substituted by fluorine, trifluoromethyl,            trifluoromethoxy or nitro,        -   and/or are optionally substituted by a radical of the            formula

-   -   -   in which        -   c represents a number 1, 2, 3 or 4,        -   and/or the carbocycles formed are optionally substituted by            a spiro-linked radical of the formula

-   -   -   in which        -   e represents a number 1, 2, 3, 4 or 5,        -   R²⁵, R²⁶, R²⁷ and R²⁸ are identical or different and            represent hydrogen, trifluoromethyl, phenyl, fluorine,            chlorine, bromine or straight-chain or branched alkyl or            alkoxy having in each case up to 4 carbon atoms,        -   or        -   R²⁵ and R²⁶ or R²⁷ and R²⁸ together form a straight-chain or            branched alkyl chain having up to 4 carbon atoms,            and their salts and N-oxides.

Very particular preference is given to compounds of the general formula(I) according to the invention,

in which

-   A represents cyclopropyl, cyclopentyl or cyclohexyl, or    -   represents thienyl or pyridyl, or A represents a radical of the        formula

-   D represents phenyl which is optionally substituted by    trifluoromethyl, fluorine, or    -   represents a radical of the formula

-   -   in which    -   R⁶ represents phenyl which is optionally substituted by        fluorine, chlorine, trifluoromethyl, trifluoromethoxy,        straight-chain or branched alkyl having in each case up to 4        carbon atoms,    -   or    -   R⁷ represents hydrogen or fluorine,    -   and    -   R⁸ represents hydrogen, fluorine, chlorine, hydroxyl, methoxy or    -   R⁷ and R⁸ together represent a radical of the formula ═O,

-   E represents cyclopropyl, cyclopentyl or cyclohexyl represents    straight-chain or branched alkyl having up to 4 carbon atoms,

-   R¹ and R² together form a straight-chain or branched alkylene chain    having up to 5 carbon atoms which has to be substituted by a    carbonyl group and/or a radical of the formula —OR¹⁹,    -   in which    -   R¹⁹ represents hydrogen    -   or represents a radical of the formula —Si(CH₃)₂C(CH₃)₃,        and their salts and N-oxides.

Moreover, processes for preparing the compounds of the general formula(I) according to the invention have been found, characterized in that

-   [A] in the case where D≠aryl, compounds of the general formula (II)

-    in which    -   A, E, R¹ and R² are as defined above,    -   with organometallic reagents in a Grignard or Wittig reaction or        in a reaction with organolithium compounds, the substituent D is        synthesized in inert solvents,    -   or in the case where D represents the radical of the formula        R⁹-T-V—X in which V is an oxygen atom,-   [B] either compounds of the general formula (III)

-    in which    -   A, E, X, R¹ and R² are as defined above,    -   are reacted with compounds of the general formula (IV)        R⁹-T-Z  (IV),    -   in which-   R⁹ and T are as defined above-   and-   Z represents halogen, preferably chlorine or bromine,-   in inert solvents, if appropriate in the presence of a base and/or    auxiliary,-   or-   [C] compounds of the general formula (III) are initially, by    reaction with compounds of the general formula (V)

-    in which-   R³⁵ represents straight-chain alkyl having up to 4 carbon atoms,-   converted into the compounds of the general formula (VI)

-    in which    -   A, E, X, R¹, R² and R³⁵ are as defined above,    -   and subsequently reacted with compounds of the general formula        (VII)        R⁹-T-V—H  (VII),    -   in which    -   R⁹, T and V are as defined above,    -   and, if appropriate, protective groups are removed,    -   or-   [D] in the case of the compounds of the general formula (Ia)

-    in which    -   A and R⁶ are as defined above,    -   R³⁶ and R³⁷ are identical or different and        -   represent cycloalkyl or cycloalkyloxy having in each case 3            to 7 carbon atoms, or        -   represent straight-chain or branched alkyl having up to 6            carbon atoms, or        -   represent phenyl which for its part are optionally            substituted by halogen, trifluoromethyl, trifluoromethoxy or            nitro, or    -   R³⁶ and R³⁷ represent one of the abovementioned spiro-linked        radicals of the formula

-   -   in which    -   W, Y, Y, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, and R³³ are as        defined above,    -   compounds of the general formula (VIII)

-   -   in which    -   R⁶, R³⁶, R³⁷, A and E are as defined above,    -   are initially oxidized to the compounds of the general formula        (LX)

-   -   in which    -   R⁶, R³⁶, R³⁷, A and E are as defined above,    -   these are, in a subsequent step, converted by asymmetric        reduction into the compounds of the general formula (X)

-   -   in which    -   R⁶, R³⁶, R³⁷, A and E are as defined above,    -   these are then converted, by the introduction of a hydroxyl        protective group, into the compounds of the general formula (XI)

-   -   in which    -   R⁶, R³⁶, R³⁷, A and E are as defined above    -   and    -   R³⁸ represents a hydroxyl protective group, preferably a radical        of the formula —SiR³⁹R⁴⁰R⁴¹,        -   in which        -   R³⁹, R⁴⁰ and R⁴¹ are identical or different and represent            C₁–C₄-alkyl,    -   which is used to prepare in a subsequent step, by        diastereoselective reduction, the compounds of the general        formula (XII)

-   -   in which    -   R⁶, R³⁶, R³⁷, R³⁸, A and E are as defined above,    -   and the compounds of the general formula (XIII)

-   -   in which    -   R⁶, R³⁶, R³⁷, R³⁸, A and E are as defined above,    -   are subsequently prepared by introducing the fluorine        substituent with fluorinating agents, such as, for example, DAST        and SF₄ derivatives,    -   and the hydroxyl protective group is then removed by customary        methods,    -   and, if appropriate, the substituents listed under D, E and/or        R¹ and R² are varied or introduced by customary methods.

By way of example, the processes according to the invention can beillustrated by the following schemes:

Suitable solvents for all processes are ethers such as diethyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulphoxide, dimethylformamide, hexamethylphosphoric triamide,acetonitrile, acetone or nitromethane. It is also possible to usemixtures of the solvents mentioned. Preference is given todichloromethane.

Suitable bases for the individual steps are the customary strongly basiccompounds. These preferably include organolithium compounds such as, forexample, N-butyllithium, sec-butyllithium, tertbutyllithium orphenyllithium, or amides such as, for example, lithium diisopropylamide,sodium amide or potassium amide, or lithium hexamethylsilylamide, oralkali metal hydrides such as sodium hydride or potassium hydride.Particular preference is given to using N-butyllithium, sodium hydrideor lithium diisopropylamide.

Suitable for the processes [B] and [C] are furthermore the customaryinorganic bases. These preferably include alkali metal hydroxides oralkaline earth metal hydroxides, such as, for example, sodium hydroxide,potassium hydroxide or barium hydroxide, or alkali metal carbonates suchas sodium carbonate or potassium carbonate or sodium bicarbonate.Particular preference is given to using sodium hydride or potassiumhydroxide.

Suitable organometallic reagents are, for example, systems such asMg/bromobenzotrifluoride and p-trifluoromethylphenyllithium.

The reductions are generally carried out with reducing agents,preferably those which are suitable for reducing ketones to hydroxylcompounds are. Particularly suitable for this purpose is the reductionwith metal hydrides or complex metal hydrides in inert solvents, ifappropriate in the presence of a trialkylborane. The reduction ispreferably carried out using complex metal hydrides such as, forexample, lithium borohydrides, sodium borohydrides, potassiumborohydrides, zinc borohydrides, lithium trialkylborohydride,diisobutylaluminium hydride or lithium aluminium hydride. The reactionis very particularly preferably carried out using diisobutylaluminiumhydride and sodium borohydride.

The reducing agent is generally employed in an amount of from 1 mol to 6mol, preferably from 1 mol to 4 mol, based on 1 mol of the compounds tobe reduced.

The reduction generally proceeds in a temperature range of from −78° C.to +50° C., preferably of from −78° C. to 0° C. in the case of DIBAH, offrom 0° C. to room temperature in the case of NaBH₄, particularlypreferably at −78° C., in each case depending on the choice of reducingagent and solvent.

The reduction generally proceeds at atmospheric pressure; however, it isalso possible to carry out the reduction at elevated or reducedpressure.

In the case [A], the process is preferably carried out using initiallycompounds of the general formula (II) in which the carbocycle R¹/R² isinitially only substituted by a group —OSiR^(I)R^(II)R^(III) in whichR^(I), R^(II) and R^(III) are identical or different and representphenyl or straight-chain or branched alkyl having up to 5 carbon atoms,and the substituent mentioned above under R¹⁹/R²⁰ is introduced bycustomary methods after the protective group has been removed.

Removal of the protective group is generally carried out in one of theabovementioned alcohols and THF, preferably methanol/THF, in thepresence of hydrochloric acid in a temperature range of from 0° C. to50° C., preferably at room temperature, and at atmospheric pressure. Inparticular cases, preference is given to removing the protective groupwith tetrabutylammonium fluoride (TBAF) in THF.

In the context of the definition given above, hydroxyl protective groupgenerally represents a protective group from the group trimethylsilyl,triisopropylsilyl, tert-butyl-dimethylsilyl, benzyl, benzyloxycarbonyl,2-nitrobenzyl, 4-nitrobenzyl, tert-butyloxycarbonyl, allyloxycarbonyl,4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, tetrahydropyranyl, formyl,acetyl, trichloroacetyl, 2,2,2-trichloroethoxycarbonyl,methoxyethoxymethyl, [2-(trimethylsilyl)ethoxy]methyl, benzoyl,4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or4-methoxybenzoyl. Preference is given to tetrahydropyranyl,tertbutyldimethylsilyl and triisopropylsilyl. Particular preference isgiven to tertbutyldimethylsilyl.

Suitable solvents for the individual steps are ethers such as diethylether, dioxane, tetrahydrofuran, glycol dimethyl ether, diisopropylether or hydrocarbons such as benzene, toluene, xylene, hexane,cyclohexane or mineral oil fractions, or halogenated hydrocarbons suchas dichloromethane, trichloromethane, carbon tetrachloride,dichloroethylene, trichloroethylene or chlorobenzene. It is alsopossible to use mixtures of the solvents mentioned.

Suitable oxidizing agents for preparing the compounds of the generalformula (IX) are, for example, nitric acid, cerium (IV) ammoniumnitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridiniumchlorochromate (PCC), pyridinium chlorochromate on basic alumina, osmiumtetroxide and manganese dioxide. Preference is given to manganesedioxide and nitric acid.

The oxidation is carried out in one of the abovementioned chlorinatedhydrocarbons and water. Preference is given to dichloromethane andwater.

The oxidizing agent is employed in an amount of from 1 mol to 10 mol,preferably from 2 mol to 5 mol, based on 1 mol of the compounds of thegeneral formula (VIII).

The oxidation generally proceeds at a temperature of from −50° C. to+100° C., preferably from 0° C. to room temperature.

The oxidation generally proceeds at atmospheric pressure. However, it isalso possible to carry out the oxidation at elevated or reducedpressure.

The asymmetric reduction to the compounds of the general formula (X) isgenerally carried out in one of the abovementioned ethers or toluene,preferably tetrahydrofuran and toluene.

The reduction is generally carried out using enantiomerically pure1R,2S-aminoindanol and borane complexes such as BH₃×THF, BH₃×DMS andBH₃×(C₂H₅)₂NC₆H₅. Preference is given to the systemborane-diethylaniline/1R,2S-aminoindanol.

The reducing agent is generally employed in an amount of from 1 mol to 6mol, preferably from 1 mol to 4 mol, based on 1 mol of the compounds tobe reduced.

The reduction generally proceeds at a temperature of from −78° C. to+50° C., preferably from 0° C. to 30° C.

The reduction generally proceeds at atmospheric pressure; however, it isalso possible to carry out the reduction at elevated or reducedpressure.

The hydroxyl protective group is introduced in one of the abovementionedhydrocarbons, dimethylformamide or THF, preferably in toluene in thepresence of lutidine in a temperature range of from −20° C. to +50° C.,preferably from −5° C. to room temperature and at atmospheric pressure.

General reagents for introducing the silyl protective group aretert-butyldimethylsilyl chloride or tert-butyldimethylsilyltrifluoromethanesulphonate. Preference is given totert-butyldimethylsilyl trifluoromethanesulphonate.

The reduction to the compounds of the general formula (XII) proceeds inone of the abovementioned hydrocarbons, preferably toluene.

The reduction to prepare the compounds of the general formula (XII) isgenerally carried out using customary reducing agents, preferably thosewhich are suitable for reducing ketones to hydroxyl compounds.Particularly suitable for this purpose is the reduction with metalhydrides or complex metal hydrides in the abovementioned inert solvents,such as, for example, toluene, if appropriate in the presence of atrialkylborane. The reduction is preferably carried out using complexmetal hydrides such as, for example, lithium borohydride, sodiumborohydride, potassium borohydride, zinc borohydride, lithiumtrialkylborohydride, diisobutylaluminium hydride, sodiumbis-(2-methoxyethoxy)aluminium hydride or lithium aluminium hydride. Thereduction is very particularly preferably carried out using sodiumbis-(2-methoxyethoxy) aluminium hydride.

The reducing agent is generally employed in an amount of from 1 mol to 6mol, preferably from 1 mol to 3 mol, based on 1 mol of the compounds tobe reduced.

The reduction generally proceeds at a temperature of from −20° C. to+110° C., preferably from 0° C. to room temperature.

The reduction generally proceeds at atmospheric pressure; however, it isalso possible to carry out the reduction at elevated or reducedpressure.

In the reduction to the compounds of the general formula (XII), smallresidues of the wrong diastereomer remain in the mother liquor. Theseresidues can be reoxidized with customary oxidizing agents such as, forexample, pyridinium chlorochromate (PCC) or activated manganese dioxide,in particular with activated manganese dioxide, to give protected (XI)and thus be recycled into the synthesis cycle without any loss in yield.

The fluorine substituent is generally introduced in one of theabovementioned hydrocarbons or methylene chloride, preferably in tolueneand under an atmosphere of protective gas.

Under SF₄ derivatives, in general diethylamino sulphur trifluoride or2,2′-bisfluoro-substituted amines such as, for example,diethyl-1,2,3,3,3-hexafluoropropylamine are prepared.

The reaction generally proceeds at a temperature of from −78° C. to 100°C., in the case of dimethylamino sulphur trifluoride preferably at from−78° C. to RT and in the case ofdiethyl-1,1,2,3,3,3-hexafluoropropylamine preferably at from roomtemperature to 80° C.

The protective group is generally removed in one of the abovementionedalcohols and THF, preferably methanol/THF in the presence ofhydrochloric acid in a temperature range of from 0° C. to 50° C.,preferably at room temperature, and atmospheric pressure. In particularcases, preference is given to removing the protective group withtetrabutylammonium fluoride (TBAF) in THF at room temperature.

The following types of reaction may be mentioned by way of example forderivatizations:

oxidations, reductions, hydrogenations, halogenation, Wittig/Grignardreactions and amidations/sulphoamidations.

Suitable bases for the individual steps are the customary strongly basiccompounds. These preferably include organolithium compounds such as, forexample, n-butyllithium, sec-butyllithium, tertbutyllithium orphenyllithium, or amides such as, for example, lithium diisopropylamide,sodium amide or potassium amide, or lithium hexamethylsilylamide, oralkali metal hydrides such as sodium hydride or potassium hydride.Particular preference is given to using N-butyllithium, sodium hydrideor lithium diisopropylamide.

Suitable bases are furthermore the customary inorganic bases. Thesepreferably include alkali metal hydroxides or alkaline earth metalhydroxides such as, for example, sodium hydroxide, potassium hydroxideor barium hydroxide, or alkali metal carbonates such as sodium carbonateor potassium carbonate or sodium bicarbonate. Particular preference isgiven to using sodium hydroxide or potassium hydroxide.

Suitable solvents for the individual reaction steps are also alcoholssuch as methanol, ethanol, propanol, butanol or tertbutanol. Preferenceis given to tertbutanol.

If required, it may be necessary to carry out some reaction steps underan atmosphere of protective gas.

The halogenations are generally carried out in one of the abovementionedchlorinated hydrocarbons, preference being given to methylene chloride.

Suitable halogenating agents are, for example, diethylamino sulphurtrifluoride (DAST), morpholino sulphur trifluoride or SOCl₂.

The halogenation generally proceeds in a temperature range of from −78°C. to +50° C., preferably from −78° C. to 0° C., in each case dependingon the choice of the halogenating agent and the solvent.

The halogenation generally proceeds at atmospheric pressure; however, itis also possible to carry out the halogenation at elevated or reducedpressure.

The compounds of the general formulae (II) and (III) are novel, and theycan be prepared by preparing,

by reaction of the compounds of the general formula (XIV)

in which

-   E is as defined above-   and-   R⁴² represents C₁–C₄-alkoxycarbonyl or aryl (D=aryl)-   with aldehydes of the general formula (XV)    A-CHO  (XV),    in which-   A is as defined above and compounds of the general formula (XVI)

-    in which-   R⁴³ and R⁴⁴, together with a carbonyl group, embrace the scope of    the meaning of R¹ and R² mentioned above,-   the compounds of the general formula (XVII)

-    in which-   A, E, R⁴², R⁴³ and R⁴⁴ are as defined above-   and, in the case of the compounds of the general formula (III),    carrying out a reduction, as described above, to furnish the    hydroxymethyl function-   and, in a last step, converting the alkoxycarbonyl group (R⁴²) by a    reduction-oxidation sequence into an aldehyde group.

Solvents which are suitable for the oxidation are ethers such as diethylether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbonssuch as benzene, toluene, xylene, hexane, cyclohexane or mineral oilfractions, or halogenated hydrocarbons such as dichloromethane,trichloromethane, carbon tetrachloride, dichloroethylene,trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine,pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphorictriamide, acetonitrile, acetone or nitromethane. It is also possible touse mixtures of the solvents mentioned. Preference is given to methylenechloride.

Suitable oxidizing agents are, for example, cerium (IV) ammoniumnitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridiniumchlorochromate (PCC), pyridinium chlorochromate on basic alumina, osmiumtetroxide and manganese dioxide. Preference is given to sulphurtrioxide-pyridine complex in DMSO/methylene chloride and pyridiniumchlorochromate on basic alumina.

The oxidizing agent is employed in an amount of from 1 mol to 10 mol,preferably from 2 mol to 5 mol, based on 1 mol of the compounds of thegeneral formula (XVII).

The oxidation generally proceeds in a temperature range of from −50° C.to +100° C., preferably from 0° C. to room temperature.

The oxidation generally proceeds at atmospheric pressure. However, it isalso possible to carry out the oxidation at elevated or reducedpressure.

The compounds of the general formulae (IV), (V), (VII), (XIV), (XV) and(XVI) are known per se or can be prepared by customary methods.

Some of the compounds of the general formulae (VI) and (XV) are known,or they are novel, in which case they can be prepared as describedabove.

The compounds of the general formulae (IX) and (X) are novel species andcan be prepared as described above.

The compounds of the general formula (VIII) are novel and can beprepared by reacting compounds of the general formulae (XVa), (XVIII)and (XIX)

-    in which-   A, E, R⁶, R³⁶ and R³⁷ are as defined above in the presence of an    acid.

Suitable solvents for preparing the compounds of the general formula(VIII) are the abovementioned ethers or alcohols. Preference is given todiisopropyl ether.

Suitable acids for preparing the compounds of the general formula (VIII)are, in general, organic carboxylic acids and inorganic acids, such as,for example, oxalic acid, maleic acid, phosphoric acid, fumaric acid andtrifluoroacetic acid. Preference is given to trifluoroacetic acid.

The acid is generally employed in an amount of from 0.1 mol to 5 mol,preferably 1 mol, based on 1 mol of the compounds of the general formula(XIX).

The reaction is generally carried out at atmospheric pressure. However,it is also possible to carry out the reaction at elevated or reducedpressure.

The reaction is generally carried out at the reflux temperature of thesolvent in question.

The compounds of the general formulae (XV) and (XIX) are known per se orcan be prepared by customary methods.

The compounds of the general formula (XVIII) are novel and can beprepared by initially preparing, by reaction of the compounds of thegeneral formula (XX)E-CO₂—R⁴⁵  (XX),in which

-   E is as defined above-   and-   R⁴⁵ represents C₁–C₄-alkyl with compounds of the general formula    (XXI)

-    in which-   R⁶ is as defined above-   in a solvent in the presence of 18-crown-6 ether, the compounds of    the general formula (XXII)

-    in which-   R⁶ and E are as defined above,-   followed by reaction with ammonium acetate in inert solvents.

Suitable solvents for the first step of the process are theabovementioned ethers and hydrocarbons, preference being given totetrahydrofuran.

Suitable solvents for the reaction with the compounds of the generalformula (XXII) are alcohols, such as, for example, methanol, ethanol,propanol or isopropanol. Preference is given to ethanol.

All steps of the process are carried out at the respective refluxtemperature of the solvent in question and at atmospheric pressure.

Some of the compounds of the general formulae (XX) and (XXI) are known,or they can be prepared by known methods.

Some of the compounds of the general formula (XXII) are novel species,and they can be prepared as described above.

The compounds of the general formulae (I) and (Ia) according to theinvention have a pharmacological activity spectrum which could not havebeen foreseen.

The compounds of the general formulae (I) and (Ia) according to theinvention have useful pharmacological properties which are superior whencompared to the prior art, in particular, they are highly effectiveinhibitors of the cholesterol ester transfer protein (CETP) and theystimulate the reverse cholesterol transport. The active compoundsaccording to the invention effect a reduction in the LDL cholesterollevel in the blood and simultaneously increase the HDL cholesterollevel. They can therefore be used for the treatment and prevention ofhypolipoproteinaemia, dyslipidaemias, hypertriglyceridaemias,hyperlipidaemias or arteriosclerosis.

The pharmacological activity of the substances according to theinvention was determined in the following test:

CETP Inhibition Test

Preparation of CETP

CETP is obtained in partially purified form from human plasma bydifferential centrifugation and column chromatography and used for thetest. For this purpose, human plasma is adjusted to a density of 1.21 gper ml using NaBr and centrifuged at 50,000 rpm at 4° C. for 18 h. Thebottom fraction (d>1.21 g/ml) is applied to a Sephadex®Phenyl-Sepharose4B (Pharmacia) column, washed with 0.15 m NaCl/0.001 m Tris HCl pH 7.4and subsequently eluted using dist. water. The CETP-active fractions arepooled, dialysed against 50 mM Na-acetate pH 4.5 and applied to aCM-Sepharose® (Pharmacia) column. Elution is subsequently carried outusing a linear gradient (0–1 M NaCl). The pooled CETP fractions aredialysed against 10 mM Tris HCl pH 7.4 and subsequently purified furtherby chromatography over a Mono Q® column (Pharmacia).

Preparation of Radioactively Labelled HDL

50 ml of fresh human EDTA plasma are adjusted to a density of 1.12 usingNaBr and centrifuged at 4° C. in a Ty 65 rotor at 50,000 rpm for 18 h.The upper phase is used to obtain cold LDL. The lower phase is dialysedagainst 3*4 l of PDB buffer (10 mM Tris/HCl pH 7.4, 0.15 mM NaCl, 1 mMEDTA, 0.02% NaN₃). Per 10 ml volume of retained material, 20 μl of3H-cholesterol (Dupont NET-725; 1 μC/μl, dissolved in ethanol!) aresubsequently added, and the mixture is incubated at 37° C. under N₂ for72 h.

The mixture is then adjusted to a density of 1.21 using NaBr andcentrifuged in a Ty 65 rotor at 20° C. and 50,000 rpm for 18 h. Theupper phase is collected and the lipoprotein fractions are purified bygradient centrifugation. To this end, the isolated labelled lipoproteinfraction is adjusted to a density of 1.26 using NaBr. In each case 4 mlof this solution are covered in centrifuge tubes (SW 40 rotor) with 4 mlof a solution of a density of 1.21 and 4.5 ml of a solution of 1.063(density solutions of PDB buffer and NaBr), and the tubes aresubsequently centrifuged in an SW 40 rotor at 38,000 rpm and 20° C. for24 h. The intermediate layer which is found between a density of 1.063and a density of 1.21 and which contains the labelled HDL is dialysedagainst 3*100 volume of PDB buffer at 4° C.

The retained material contains radioactively labelled ³H-CE-HDL, whichis used for the test adjusted to approximately 5×10⁶ cmp per ml.

CETP Test

To test the CETP activity, the transfer of ³H-cholesterol ester fromhuman HD-lipoproteins to biotinylated LD-lipoproteins is measured.

The reaction is terminated by addition of Streptavidin-SPA® beads(Amersham) and the transferred radioactivity is directly determined in aliquid scintillation counter.

In the assay mixture, 10 μl of HDL-³H-cholesterol ester (˜50,000 cpm)with 10 μl of Biotin-LDL (Amersham) in 50 mM Hepes/0.15 m NaCl/0.1%bovine serum albumin/0.05% NaN₃ pH 7.4 are incubated with 10 μl of CETP(1 mg/ml) and 3 μl of a solution of the substance to be tested(dissolved in 10% DMSO/1% BSA) at 37° C. for 18 h. 200 μl of the SPAstreptavidin bead solution (TRKQ 7005) are subsequently added, themixture is incubated with shaking for another 1 h and subsequentlymeasured in a scintillation counter. The controls used are correspondingincubations with 10 μl of buffer, 10 μl of CETP at 4° C. and 10 μl ofCETP at 37° C.

The activity which is transferred in the control experiments with CETPat 37° C. is classified as 100% transfer. The substance concentration atwhich this transfer is reduced by half is stated as the IC₅₀ value.

In Table A below, the IC₅₀ values (mol/1) for CETP inhibitors are given:

TABLE A Example No. IC₅₀ value (mol/l) 1 1 × 10⁻⁸Ex Vivo Activity of the Compounds According to the Invention

Syrian gold hamsters, which have been bred in our own laboratory, areanaesthetized after 24 hours of fasting (0.8 mg/kg of atropine, 0.8mg/kg of Ketavet® s.c., 30′ later 50 mg/kg of Nembutal i.p.). Thejugular vein is subsequently exposed and cannulated. The test substanceis dissolved in a suitable solvent (usually adalate placebo solution: 60g of glycerol, 100 ml of H₂O, ad 1000 ml PEG-400) and administered tothe animals via a PE catheter, which is introduced into the jugularvein. The same volume of solvent without test substance is administeredto the control animals. The vein is subsequently tied off and the woundis closed.

The test substances can also be administered p.o. by dissolving thesubstances in DMSO and suspending them in 0.5% tylose and administeringthem perorally using a pharyngeal tube. Identical volumes of solventwithout test substance are administered to the control animals.

At different intervals—up to 24 hours after administration—blood samplesare taken from the animals by puncture of the retro-orbital venousplexus (approximately 250 μl). Coagulation is completed by incubation at4° C. overnight, and the samples are subsequently centrifuged at 6000×gfor 10 minutes. The CETP activity is determined in the resulting serumusing the modified CETP test. The transfer of ³H-cholesterol ester fromHD-lipoproteins to biotinylated LD-lipoproteins is measured as describedabove for the CETP test.

The reaction is terminated by addition of Streptavidin-SPA^(R) beads(Amersham), and the transferred radioactivity is directly determined ina liquid scintillation counter.

The test protocol is carried out as described under “CETP test”.However, to test the serum, only 10 μl of CETP are replaced by 10 μl ofthe appropriate serum samples. Corresponding incubations of sera ofuntreated animals serve as controls.

The activity that is transferred in the control experiments usingcontrol sera is classified as 100% transfer. The substance concentrationat which this transfer is reduced by half is stated as the ED₅₀ value.

In Vivo Activity of the Compounds According to the Invention

In experiments for determining the oral activity on lipoproteins andtriglycerides, test substance, dissolved in DMSO and suspended in 0.5%tylose, is administered perorally by means of a pharyngeal tube toSyrian gold hamsters which have been bred in our own laboratory. Todetermine the CETP activity, blood samples (approximately 250 μl) aretaken by retro-orbital puncture prior to the start of the experiment.The test substances are subsequently administered perorally using apharyngeal tube. Identical volumes of solvent without test substance areadministered to the control animals. Subsequently, the animals have tofast and at different intervals—up to 24 hours after administration ofthe substances—blood samples are taken by puncture of the retro-orbitalvenous plexus.

Coagulation is completed by incubation at 4° C. overnight, and thesamples are subsequently centrifuged at 6000×g for 10 minutes. Thecontent of cholesterol and triglycerides in the resulting serum isdetermined using modified commercially available enzyme tests(cholesterol enzymatic 14366 Merck, triglycerides 14364 Merck). Serum isdiluted in a suitable manner with normal saline solution.

100 μl of serum dilution and 100 μl of test substance are transferredinto 96-well plates and incubated at room temperature for 10 minutes.The optical density is subsequently determined at a wavelength of 492 nmusing an automatic plate reader. The triglyceride and cholesterolconcentrations of the samples are determined with the aid of a standardcurve measured in parallel.

The determination of the HDL-cholesterol content is carried out afterprecipitation of the ApoB-containing lipoproteins using a reagentmixture (Sigma 352-4 HDL cholesterol reagent) in accordance with theinstructions of the manufacturer.

In Vivo Activity in Transgenic hCETP Mice

The substances to be tested were administered to transgenic mice, whichwere bred in our own laboratory (Dinchuck, Hart, Gonzalez, Karmann,Schmidt, Wirak; BBA (1995), 1295, 301), via the feed. Prior to thebeginning of the experiment, blood samples were taken retro-orbitallyfrom the mice to determine cholesterol and triglycerides in the serum.The serum was obtained as described above for hamsters by incubation at4° C. overnight and subsequent centrifugation at 6000×g. After one week,blood samples were again taken from the mice to determine lipoproteinsand triglycerides. The change of the measured parameters are expressedas a change in percent based on the initial value.

The invention furthermore relates to the combination ofhetero-tetrahydroquinolines of the general formula (I) with aglucosidase and/or amylase inhibitor for the treatment of familialhyperlipidaemias, of obesity (adipositas) and of diabetes mellitus.Glucosidase and/or amylase inhibitors in the context of the presentinvention are, for example, acarbose, adiposine, voglibose, miglitol,emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688,trestatin, pradimicin-Q and salbostatin.

Preference is given to the combination of acarbose, miglitol, emiglitateor voglibose with one of the abovementioned compounds of the generalformula (I) according to the invention.

Furthermore, the compounds according to the invention can be combinedwith cholesterol-lowering vastatines or ApoB-lowering principles, inorder to treat dyslipidaemias, combined hyperlipidaemias,hypercholesterolaemias or hypertriglyceridaemias.

The abovementioned combinations can also be used for primary orsecondary prevention of coronary heart diseases (for example myocardialinfarction).

Vastatines in the context of the present invention are, for example,lovastatin, simivastatin, pravastatin, fluvastatin, atorvastatin andcerivastatin. ApoB-lowering agents are, for example, MTP inhibitors.

Preference is given to the combination of cerivastatin or ApoBinhibitors with one of the abovementioned compounds of the generalformula (I) according to the invention.

The novel active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable carriers or solvents. Inthis case the therapeutically active compound should in each case bepresent in a concentration of from approximately 0.5 to 90% by weight ofthe total mixture, i.e. in amounts which are sufficient in order toachieve the dosage range indicated.

The formulations are prepared, for example, by extending the activecompounds using solvents and/or carriers, if appropriate usingemulsifiers and/or dispersants, it optionally being possible, forexample, to use organic solvents as auxiliary solvents if the diluentused is water.

Administration is carried out in a customary manner, intravenously,orally, parenterally or perlingually, in particular orally.

In the case of parenteral administration, solutions of the activecompound can be used by employing suitable liquid carrier materials.

In general, it has proved advantageous, in the case of intravenousadministration, to administer amounts of from approximately 0.001 to 1mg/kg, preferably approximately 0.01 to 0.5 mg/kg, of body weight toachieve effective results, and in the case of oral administration thedosage is approximately 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg, ofbody weight.

In spite of this, if appropriate it may be necessary to depart from theamounts mentioned, namely depending on the body weight or on the type ofadministration route, on the individual reaction towards the medicament,the manner of its formulation and the time at or interval during whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the abovementioned minimum amount, while in othercases the upper limit mentioned has to be exceeded. In the case of theadministration of relatively large amounts, it may be advisable todivide these into several individual doses over the course of the day

Abbreviations Used:

-   Cy=Cyclohexane-   EA=Ethyl acetate-   PE=Petroleum ether-   THF=Tetrahydrofuran-   DAST=Dimethylaminosulphur trifluoride-   PTA=para-toluenesulphonic acid-   PDC=Pyridinium dichromate-   PE/EA=Petroleum ether/ethyl acetate-   Tol=Toluene    Starting Materials

EXAMPLE I2-Cyclopentyl-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenzoyl)-1,4,5,6,7,8-hexahydro-quinolin-5-one

1.425 g (5.03 mol) of3-amino-3-cyclopentyl-1-(4-trifluoromethylphenyl)-propenone aresuspended in 25 ml of diisopropyl ether. 740 mg (5.28 mol) of dimedone,0.39 ml (5.03 mol) of trifluoroacetic acid and then 592 mg (5.28 mol) ofthiophen-3-aldehyde are added. The mixture is heated at reflux for 2hours, which immediately gives a yellow solution from which, after 30minutes, product precipitates out. The mixture is cooled and the productis filtered off with suction and washed with diisopropyl ether. Theproduct is recrystallized from acetonitrile.

Yield: 741 mg, m.p. 228–229° C.

The mother liquor gives another 230 mg of pure product.

The compounds listed in Table I are prepared analogously to theprocedure of Example I:

TABLE I Ex. m.p.: No. Structure (° C.) II

144–47  III

200–206

PREPARATION EXAMPLES Example 12-Cyclopentyl-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenzoyl)-5,6,7,8-tetrahydro-quinolin-5-one

1.21 g (2.42 mmol) of the compound from Example I are dissolved in 35 mlof dichloromethane and, after addition of 6.8 g of manganese dioxide,stirred for 2 hours. The mixture is filtered off with suction usingCelite as a filtration aid and is concentrated. The evaporation residueis stirred with acetonitrile, filtered off with suction and washed withacetonitrile. This gives 1.045 g of crystals of m.p.: 236–238° C.

The compounds listed in Table 1 are prepared analogously to theprocedure of Example 1:

TABLE 1 Ex. m.p. No. Structure (° C.) 2

221–224 3

185–186

Example 42-Cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenzoyl)-5,6,7,8-tetrahydroquinoline

(1R,2S)-Aminoindan-2-ol are suspended in 0.4 ml of THF. At RT,N,N-boranediethylaniline complex (Aldrich) are added dropwise. All isdissolved and stirred at RT for 1 hour. The mixture is then stirred at0° C. for 15 minutes. The compound from Example 1 is dissolved in 16 mlof THF and added dropwise at from 0 to 5° C. over a period of 10minutes. The mixture is then stirred at 0° C. for 30 min and at RT for 4hours. At from −10° C. to 0° C., 35 ml of 1,2 ethanediol are carefullyadded dropwise, the mixture is stirred for 30 minutes and concentrated,the residue is dissolved in ethyl acetate, the solution is washed with 1N HCl, then with sat. sodium bicarbonate solution, then with sat. sodiumchloride solution, dried over sodium sulphate, filtered andconcentrated. This gives 1.17 g of a crystalline compound. The compoundis dissolved in hot cyclohexane and the mixture is filtered off. Oncooling, the compound crystallizes out. The mixture is filtered off withsuction and the compound is washed and dried at 70° C. under reducedpressure.

Yield: 0.7 g

Concentration of the mother liquor (column:toluene:ethyl acetate 20.1),dissolving the residue in methylene chloride and reconcentrating thesolution gives a further 0.27 g of crystals.

Overall yield: 970 mg (87.3%) of m.p.: 179–182° C.

Example 55-tertButyldimethylsilyloxy-2-cyclopentyl-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoro-methylbenzoyl)-5,6,7,8-tetrahydroquinoline

Under argon, 0.8 g (1.6 mmol) of the compound from Example 4 isdissolved in 6.4 ml of toluene and, at from −5° to −10° C. admixeddropwise with 0.69 g (6.4 mmol) of 2,6-lutidine. The mixture is stirredfor 15 minutes. At the same temperature, 0.86 g (3.2 mmol) oftertbutyl-dimethylsilyl trifluoromethanesulphonate in 1.2 ml of tolueneis then added dropwise. The mixture is stirred at from −5° C. to −10° C.for 15 minutes and then at room temperature for 2 hours.

The mixture is diluted with toluene and washed successively with 2.6 mlof 10% ammonium chloride solution, 7 times with in each case 3.5 ml of0.1 N HCl, once with 1.5 ml of sat. sodium bicarbonate solution and oncewith 3.5 ml of sat. sodium chloride solution. The mixture is then driedand concentrated and concentrated once with ethanol.

This gives 1.0 g The product is recrystallized from a little ethanol,filtered off with suction, washed and dried at 60° C. under reducedpressure.

Yield: 716 mg, m.p. 147–148° C.

The mother liquor is concentrated and the residue is treated withethanol and filtered off with suction. This gives another 60 mg.

Example 65-(S)-tertButyldimethylsilyloxy-2-cyclopentyl-7,7-dimethyl-4-(3-thienyl)-3-[(R)-hydroxy-(4-trifluoromethylphenyl)]methyl-5,6,7,8-tetrahydroquinoline

0.69 g (1.124 mmol) of the compound from Example 5 is dissolved in 5 mlof toluene; at 0° C., 1.40 g (4.496 mmol) of RED-A1 are added dropwiseand the mixture is stirred at 0° C. for 30 minutes and at RT for 1 hour.At 0° C., 0.85 ml of methanol is slowly added dropwise, and the yellowsolution is stirred at 0° C. for 30 minutes. 0.73 ml of a 20% strengthpotassium sodium tartrate solution is then added dropwise, the mixtureis filtered off with suction, the filtrate is washed with toluene and alittle 20% strength potassium sodium tartrate solution, separated off,washed once with sat. sodium bicarbonate solution and twice with sat.sodium chloride solution, dried over sodium sulphate and concentrated.This gives 850 mg of an oil which comprises the two possiblediastereomers which are separated on a 400 ml silica gel column. Theproduct is eluted with petroleum ether, petroleum ether/ethyl acetate20:1, 10:1.

This gives 86.2 mg of the wrong diastereomer and 356.2 mg of the rightdiastereomer.

Example 75-(S)-tertButyldimethylsilyloxy-2-cyclopentyl-7,7-dimethyl-3-[5-fluoro-(4-trifluoro-methylphenyl)-methyl]-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline

320 mg (0.52 mmol) of the compound from Example 6 are dissolved in 7 mlof dichloromethane and, at −15° C., treated with 140 mg (0.86 mmol) ofDAST. After 30 minutes, the reaction is carried out at from −15° C. to−10° C., methylene chloride and water are added, the phases areseparated, the aqueous phases extracted once with methylene chloride,and the organic phases are washed once with sat. sodium chloridesolution and with a little sat. sodium bicarbonate solution, dried andconcentrated.

Crystallization is carried out using methanol. The product is filteredoff with suction and washed.

Yield: 57.8 mg of m.p.: 171–172° C.

Example 82-Cyclopentyl-3-[fluoro-(4-trifluoromethylphenyl)methyl]-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline

111 mg (0.18 mmol) of the compound from Example 7 are dissolved in 1.4ml of methanol and admixed with 0.9 ml of THF and 0.98 ml of 5 Nhydrochloric acid. The mixture is stirred at 40° C. for 4 hours. Themixture is concentrated, admixed with water, ammonia solution and ethylacetate, the phases are separated and the aqueous phases extracted oncewith ethyl acetate. The organic phases are washed once with sodiumchloride solution, dried and concentrated. this gives 82 mg as an oil.

The product is dissolved in petroleum ether and a little methylenechloride and applied to a column, eluted with petroleum ether: ethylacetate 30.1, 20.1, 10.1, and 2 fractions are concentrated.

The crystalline solid is filtered off with suction with a littlen-heptane and dried under reduced pressure.

This gives 37.1 mg (41% of theory) of a colourless substance of m.p.:157–159° C.

Example 92-Cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(trifluoromethylbenzyl)-5,6,7,8-tetrahydroquinoline

20 mg (0.04 mmol) of the compound from Example 8 are dissolved in 3 mlof toluene and, at −20° C., admixed with 0.27 ml of Dibal-H in tolol.The mixture is stirred at −20° C. for 2 hours. The mixture is admixedwith 10 ml of 20% potassium sodium tartrate solution and ethyl acetateand stirred for some time, the phases are separated, the aqueous phaseis extracted 2× with ethyl acetate, and the organic phases are dried andconcentrated.

17 mg of the title compound are dissolved in methylene chloride, appliedto a column and eluted with toluene.

FR 1—1:5.5 mg NMR

R_(f) value: TLC aluminium foil silica gel 60 F₂₅₄, layer thickness 0.2mm 0.40 (mobile phase:petroleum ether/ethyl acetate 10:1)

R_(f)=0.45; mobile phase toluene/ethyl acetate 10:1.

The compounds listed in Table 1 are prepared analogously to theprocedures given above:

Ex. No. Structure Isomer R_(f) 10

isomer 1 0.67^(a)) 11

isomer 2 0.52^(a)) ^(a))EtOAc/petroleum ether 1:1

1. A pyridinyl-tetrahydroquinolin-5-one compound of the formula:

in which A represent pyridinyl, which is optionally substituted up to 5times by identical or different substituents from the group consistingof halogen, nitro, hydroxyl, trifluorometbyl, trifluoromethoxy andstraight-chain or branched alky, acyl, hydroxyalkyl or alkoxy having ineach case up to 7 carbon atoms, or by a group of the formula —NR³R⁴, inwhich R³ and R⁴ are identical or different and represent hydrogen, phenyor straight-chain or branched alkyl having up to 6 carbon atoms, Drepresents aryl having 6 to 10 carbon atoms which is optionallysubstituted by phenyl, nitro, halogen, trifluorornethyl ortrifluoromethoxy, or represents a radical of the formula

 in which R⁵, R⁶ and R⁹ independently of one another representcycloalkyl having 3 to 6 carbon atoms, or represent aryl having 6 to 10carbon atoms, which optionally substituted up to 5 times by identical ordifferent substituents from the group consisting of halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, andstraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl having in each case up to 6 carbon atoms, by aryl orby trifluoromethyl-substituted aryl having in each case 6 to 10 carbonatoms, and/or by a group of the formula —OR¹⁰, —SR¹¹, —SO₂R¹² or—NR¹³R¹⁴  in which R¹⁰, R¹¹ and R¹² independently of one anotherrepresent aryl having 6 to 10 carbon atoms which for its part issubstituted up to 2 times by identical or different substituents fromthe group consisting of phenyl, halogen and straight-chain or branchedalkyl having up to 6 carbon atoms, R¹³ and R¹⁴ are identical ordifferent and have the meaning of R³ and R⁴ given above, R⁷ representshydrogen or halogen, and R⁸ represents hydrogen, halogen, azido,trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branchedalkoxy or alkyl having in each case up to 6 carbon atoms or a radical ofthe formula —NR¹⁵R¹⁶, in which R¹⁵ and R¹⁶ are identical or differentand have the meaning of R³ and R⁴ given above, or R⁷ and R⁸ togetherform a radical of the formula ═O or ═NR¹⁷, in which R¹⁷ representshydrogen or straight-chain or branched alkyl, alkoxy or acyl having ineach case up to 6 carbon atoms, L represents a straight-chain orbranched alkylene or alkenylene chain having in each case up to 8 carbonatoms which are optionally substituted up to 2 times by hydroxyl, T andX are identical or different and represent a straight-chain or branchedalkylene chain having up to 8 carbon atoms, or T or X represents a bond,V represents an oxygen or sulphur atom or represents an —NR¹⁸ group, inwhich R¹⁸ represents hydrogen or straight-chain or branched alkyl havingup to 6 carbon atoms or phenyl, and E represents cycloalkyl having 3 to8 carbon atoms, or represents straight-chain or branched alkyl having upto 8 carbon atoms which is optionally substituted by cycloalkyl having 3to 8 carbon atoms or hydroxyl, or represents phenyl which is optionallysubstituted by halogen or trifluoromethyl, and wherein thetetrahydroquinolin-5-yl moiety is optionally substituted by one or morealkyl groups having a collective total of 1–3 carbon atoms, or a salt ofsaid compound or an N-oxide of said compound or said salt.
 2. Thecompound according to claim 1, in which A represents pyridinyl, which isoptionally substituted up to 2 times by identical or differentsubstituents from, the group consisting of fluorine, chlorine, bromine,amino, hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain orbranched alkyl, and alkoxy having in each case up to 6 carbon atoms, Drepresents phenyl which is optionally substituted by nitro, fluorine,chlorine, bromine. phenyl, trifluoromethyl or trifluoromethoxy, orrepresents a radical of the formula

 in which R⁵, R⁶ and R⁹ independently of one another representcyclopropyl, cyclopentyl or cyclohexyl, or represent phenyl, which isoptionally substituted up to 3 times by identical or differentsubstituents from the group consisting of fluorine, chlorine, bromine,trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy,straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl having in each case up to 4 carbon atoms,trifluoromethyl-substituted phenyl and phenyl, R⁷ represents hydrogen,fluorine, chlorine or bromine, and R⁸ represents hydrogen, fluorine,chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy,straight-chain or branched alkoxy or alkyl having in each case up to 5carbon atoms or a radical of the formula —NR⁵R⁶, in which R¹⁵ and R¹⁶are identical or different and represent hydrogen, phenyl orstraight-chain or branched alkyl having up to 4 carbon atoms, or R⁷ andR⁸ together form a radical of the formula ═O or ═NR¹⁷, in which R¹⁷represents hydrogen or straight-chain or branched alkyl, alkoxy or acylhaving in each ease up to 4 carbon atoms, L represents a straight-chainor branched alkylene or alkenylene chain having in each case up to 6carbon atoms which are optionally substituted up to 2 times by hydroxyl,T and X are identical or different and represent a sfraight-chain orbranched alkylene chain having up to 6 carbon atoms, or T or Xrepresents a bond, V represents an oxygen or sulphur atom or representsa group of the formula —NR¹⁸, in which R¹⁸ represents hydrogen orstraight-chain or branched aikyl having up to 4 carbon atoms or phenyl,E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, orrepresents straight-chain or branched all having up to 6 carbon atomswhich is optionally substituted by cyclopropyl, -butyl, -hexyl, -pentyl,-heptyl or by hydroxyl, or represents phenyl which is optionallysubstituted by fluorine, chlorine or trifluoromethyl, and wherein thetetrahydroquinolin-5-yl moiety is optionally substituted by one or morealkyl groups having a collective total of 1–3 carbon atoms, or a salt ofsaid compound or an N-oxide of said compound or said salt.
 3. Thecompound according to claim 1, in which A represents pyridyl, which isoptionally substituted up to 2 times by identical or differentsubstituents from the group consisting of fluorine, chlorine, bromine,hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain orbranched all or alkoxy having in each case up to 5 carbon atoms, Drepresents phenyl which is optionally substituted by nitro,trifluoromethyl, phenyl, fluorine, chlorine or bromine, or represents aradical of the formula

 in which R⁵, R⁶ and R⁹ independently of one another representcyclopropyl, cyclopentyl or cyclohexyl, or represent phenyl or naphthyl,which are optionally substituted up to 2 times by identical or differentsubstituents from the group consisting of fluorine, chlorine,trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy andstraight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy oralkoxycarbonyl having in each case up to 4 carbon atoms, R⁷ representshydrogen or fluorine, and R⁸ represents hydrogen, fluorine, chlorine,bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, orstraight-chain or branched alkoxy or alkyl having in each case up to 4carbon atoms or a radical of the formula —NR¹⁵R¹⁶, in which R¹⁵ and R¹⁶are identical or different and represent hydrogen or straight-chain orbranched all having up to 3 carbon atoms, or R⁷ and R⁸ togetherrepresent a radical of the formula ═O, L represents a straight-chain orbranched alkylene or alkenylene chain having in each case tip to 5carbon atoms which are optionally substituted up to 2 times by hydroxyl,T and X are identical or different and represent a straight-chain orbranched alkylene chain having up to 3 carbon atoms, or T or Xrepresents a bond, V represents an oxygen or sulphur atom or a group ofthe formula —NR¹⁸, in which R⁸ represents hydrogen or straight-chain orbranched alkyl having up to 3 carbon atoms, E represents cyclopropyl,cyclopentyl or cyclohexyl or phenyl which is optionally substituted byfluorine or trifluoromethyl, or represents straight chain or branchedalkyl having up to 4 carbon atoms which is optionally substituted byhydroxyl, and wherein the tetrahydroquinolin-5-yl moiety is optionallysubstituted by one or more alkyl groups having a collective total of 1–3carbon atoms, or a salt of said compound or an N-oxide of said compoundor said salt.
 4. The compound according to claim 1, in which Arepresents pyridinyl, D represents phenyl which is optionallysubstituted by trifluoromethyl, fluorine, or represents a radical of theformula

 in which R⁶ represents phenyl which is optionally substituted byfluorine, chlorine, trifluoromethyl, trifluoromethoxy, straight-chain orbranched alkyl having in each case up to 4 carbon atoms. R⁷ representshydrogen or fluorine, and R⁸ represents hydrogen, fluorine, chlorine,hydroxyl, methoxy, or R⁷ and R⁸ together represent a radical of theformula ═O, E represents cyclopropyl, cyclopentyl or cyclohexyl, orrepresents straight-chain or branched all having up to 4 carbon atoms,and wherein the tetrahydroquinolin-5-yl moiety is optionally substitutedby one or more alkyl groups having a collective total of 1–3 carbonatoms, or a salt of said compound or an N-oxide of said compound or saidsalt.
 5. The compound according to claim 1, which has the formula:

or a salt of said compound or an N-oxide of said compound or said salt.6. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and an effective amount of thepyridinyl-tetrahydroquinolin-5-one compound according to claim 1, or asalt or an N-oxide of said compound or said salt.
 7. A method oftreating hyperlipoproteinanaemia comprising administering to a patientin need thereof an effective amount therefor of the compositionaccording to claim
 6. 8. A method of treating arteriosclerosiscomprising administering to a patient in need thereof an effectiveamount therefor of the composition according to claim
 6. 9. A method oftreating dislipidaemia comprising administering to a patient in needthereof an effective amount therefor of the composition according toclaim 6.